DNA repair is essential for maintenance of genome integrity in all organisms. Numerous DNA repair systems evolved to eliminate a broad variety of DNA lesions caused by exogenous agents or genotoxic products of metabolism. In normal cells, the specificities of different DNA repair mechanisms overlap to assure efficient genome protection. However, cancer cells often lose some DNA repair pathways due to intrinsic genome instability. In this case, cancer cell viability depends on the remaining alternative DNA repair mechanisms. Poly (ADP-ribose) polymerase 1 (PARP1), a protein involved in DNA damage signaling and repair of DNA single-stranded breaks (SSB), is essential for viability of cancer cells that are deficient in the homologous recombination (HR) pathway. Furthermore, hereditary breast cancer and ovarian cancer cells, which often carry mutations in HR proteins BRCA1 or BRCA2, can be eliminated using PARP1 inhibitors with a minimal harm to normal cells with at least one copy of functional BRCA1/2 genes.
BRCA1/2-deficient cancer cells are not viable when RAD52 protein is inactivated. In addition, RAD52 knockdown also causes lethality to human cells deficient in PALB2 (partner and localizer of BRCA2) and five RAD51 paralogs, including RAD51C. Mutations in PALB2 and RAD51C also contribute to hereditary breast and ovarian cancer. Previously, inviability of double mutations in RAD52 and RAD51C genes was reported in chicken DT-40 cells. Inactivation of PARP1 and RAD52 causes lethality of BRCA1/2-deficient and PALB2-deficient cells through different mechanisms. Inactivation of PARP1 causes disruption of repair of DNA SSBs. During DNA replication, unrepaired SSBs may cause formation of DNA double-stranded breaks (DSBs) or stalled replication forks, which are repaired by the HR pathway. BRCA1/2/PALB2 constitute the major sub-pathway of HR; mutations in these proteins incapacitates HR making hereditary breast and ovarian cancer cells vulnerable to PARP1 inhibitors. However, recent data have demonstrated that, in addition to the BRCA1/2/PALB2 sub-pathway, the secondary HR sub-pathway operates in mammalian cell that depends on RAD52 protein. In normal mammalian cells, this pathway plays a minor role, as RAD52−/− mice are viable and fertile and do not display DNA damage sensitivity, abnormalities, or significant cancer predisposition. However, this sub-pathway becomes essential for viability in cells that lack the BRCA1/2/PALB2 sub-pathway.
There is a need in the art for novel compositions and methods that are useful for the treatment of cancers through inhibition of RAD52 in a mammal. The present invention addresses this unmet need.